Buccal drug delivery systems,advanced drug delivery systems

buccal drug delivery systems

1. A seminar onA seminar on
Mucoadhesive (Buccal) drug delivery Mucoadhesive (Buccal) drug delivery
systemsystem
Presented by :Presented by : Presented To :Presented To :
Mr.Bhos Amol Mr.Bhos Amol Mr.V.J.JAMAKANDIMr.V.J.JAMAKANDI
M.PharmM.Pharm
Part-IPart-I
One cannot hope to discover new oceans of One cannot hope to discover new oceans of
opportunity unless he has the courage to lose sight of the opportunity unless he has the courage to lose sight of the
shore.shore.
David J. HaussDavid J. Hauss
ChairmanChairman. . APPS Focus APPS Focus
CompanyCompany

2. ContentsContents::

Buccal drug delivery systemsBuccal drug delivery systems

ConceptsConcepts
Advantages and disadvantagesAdvantages and disadvantages

Structure of oral mucosaStructure of oral mucosa
Transmucosal permeabilityTransmucosal permeability

Mucosal membrane modelsMucosal membrane models

Permeability enhancersPermeability enhancers

In vitroIn vitro and and in vivoin vivo methods of buccal absorption. methods of buccal absorption.

3. History of Buccal DeliveryHistory of Buccal Delivery
• Discovery - 1879
• US Reg 1982 - Isosorbide dinitrate
- Ergot alkaloids
- Nitroglycerine
- Nicotine
- Testosterone & derivatives
• 1993 - Fentanyl, “Actiq” (Anesta)
• Sept 2006 - Fentanyl, “Fentora” (CIMA)

4. ConceptConcept
►Within the oral mucosal cavity, the buccalWithin the oral mucosal cavity, the buccal
region offers an attractive route of administration for region offers an attractive route of administration for
systemic drug delivery.systemic drug delivery.
►Within the oral mucosal cavity, delivery of drugs is Within the oral mucosal cavity, delivery of drugs is
classified into three categories:classified into three categories:
1) sublingual delivery1) sublingual delivery
2) buccal delivery2) buccal delivery
3) local delivery3) local delivery

5. Why Oral?Why Oral?
Non - Oral
24% Oral
76%
Top 100 Drugs - U.S. Market Value

6. Technology and Product FocusTechnology and Product Focus
Drug Delivery SystemsDrug Delivery Systems
Source: IMS America - Drug delivery based products
Oral CROral CR
60%60%
Implant
10%
Inhalation
27%
Transdermal
8%
All Other
2%

7. ►Adhesion :Adhesion :
the state in which two materials, at least one of the state in which two materials, at least one of
which being biological in nature, are held together for an which being biological in nature, are held together for an
extended period of time, by interfacial forces.extended period of time, by interfacial forces.
►The biological surface can be epithelial tissue or it can be mucus The biological surface can be epithelial tissue or it can be mucus
coat on the surface of tissue.coat on the surface of tissue.
►If adhesive attachment is to a mucus coat, the phenomenon is If adhesive attachment is to a mucus coat, the phenomenon is
referred as mucoadhesion.referred as mucoadhesion.
►Bioadhesion Bioadhesion ::
It is defined as ‘ a substance that is capable of It is defined as ‘ a substance that is capable of
interacting with biological material & being retained on them or interacting with biological material & being retained on them or
holding them together for extended period of time’.holding them together for extended period of time’.

8. ►The goal of the development of bioadhesive is to The goal of the development of bioadhesive is to
improve biological adhesives, which are both durable improve biological adhesives, which are both durable
where required and degradable where necessary and where required and degradable where necessary and
non toxic at all.non toxic at all.
►Mucoadhesive drug delivery system utilize the Mucoadhesive drug delivery system utilize the
property of bioadhesion of certain water soluble property of bioadhesion of certain water soluble
polymer which become adhesive on hydration and & polymer which become adhesive on hydration and &
hence can be used for targeting a drug to a particular hence can be used for targeting a drug to a particular
region of the body for extended period of time.region of the body for extended period of time.

9. ►The mucosal layer lines a number of regions of the The mucosal layer lines a number of regions of the
body for attachment of any bioadhesive system body for attachment of any bioadhesive system
includes mainly,includes mainly,
Buccal Buccal delivery systemdelivery system
SublingualSublingual delivery system delivery system
VaginalVaginal delivery system delivery system
Rectal Rectal delivery systemdelivery system
NasalNasal delivery system delivery system
OcularOcular delivery system delivery system
GITGIT delivery system delivery system

10. ADVANTAGES OF BDDSADVANTAGES OF BDDS
1.1.BDDS especially for metabolically unstable drugs such as peptides.BDDS especially for metabolically unstable drugs such as peptides.
2.2.The mucosa is well supplied with both vascular and lymphatic drainage The mucosa is well supplied with both vascular and lymphatic drainage
which gives :which gives :
1.1.Rapid onset of actionRapid onset of action
2.2.High blood levels High blood levels
3.3.Excellent accessibility.Excellent accessibility.
3.3.Because of its natural function, the buccal mucosa is less sensitive to Because of its natural function, the buccal mucosa is less sensitive to
irritation & damage.irritation & damage.
4.4.Provides an alternative to insufficient oral delivery & inconvenient Provides an alternative to insufficient oral delivery & inconvenient
parenteral delivery of hydrophilic macromolecular drugs such as parenteral delivery of hydrophilic macromolecular drugs such as
peptides and proteins.peptides and proteins.
5.5.A number of small mol. wt.drugs including nitrates, morphine, fentanyl A number of small mol. wt.drugs including nitrates, morphine, fentanyl
& buprenorphine have permit through oral mucosa.& buprenorphine have permit through oral mucosa.

11. 66Ease of administration.Ease of administration.
77Permits localization of the drug for prolonged period of time.Permits localization of the drug for prolonged period of time.
88Can be administered to unconscious patient.Can be administered to unconscious patient.
99Avoidance of first pass metabolism.Avoidance of first pass metabolism.
1010Reduction in dose with dose dependent side effect.Reduction in dose with dose dependent side effect.
1111Selective use of therapeutic agents like peptides, proteins & Selective use of therapeutic agents like peptides, proteins &
ionized species can be achieved.ionized species can be achieved.
1212Drugs unstable in GIT.Drugs unstable in GIT.
1313Patient compliance.Patient compliance.

12. Limitations of BDDSLimitations of BDDS
1.1.The major limitation to buccal delivery is low The major limitation to buccal delivery is low
flux through the tissue resulting in low flux through the tissue resulting in low
bioavailability.bioavailability.
2.2.Small surface area & low tissue permeability.Small surface area & low tissue permeability.
3.3.Drugs which :Drugs which :
1.1.Irritate the mucosaIrritate the mucosa
2.2.Have a bitter or unpleasant taste Have a bitter or unpleasant taste
3.3.Obnoxious odour. Obnoxious odour.
Cannot be administered by this route.Cannot be administered by this route.
4.4.Drugs unstable at buccal pH.Drugs unstable at buccal pH.

13. 55Small dose requirement.Small dose requirement.
66Only drugs absorbed by passive diffusion can be Only drugs absorbed by passive diffusion can be
administered.administered.
77Eating & drinking becomes restricted.Eating & drinking becomes restricted.
88Patient variability.Patient variability.
99over hydration of polymer resulting in slippery over hydration of polymer resulting in slippery
surface.surface.

14. ORAL CAVITYORAL CAVITY

16. Overview of the oral mucosaOverview of the oral mucosa
►A. StructureA. Structure : :
►The oral mucosa is composed of an;The oral mucosa is composed of an;
outermost layer of outermost layer of stratified squamous epitheliumstratified squamous epithelium
Below this lies a Below this lies a basement membrane, a lamina basement membrane, a lamina
propriapropria..
Followed by the Followed by the submucosasubmucosa as the innermost layer as the innermost layer

17. Epithelium
Lamina Propria
Submucosa

18. STRUCTURE OF THE ORAL STRUCTURE OF THE ORAL
MUCOSA:-MUCOSA:-

19. ►Epithelium :Epithelium :
The oral ep. Which measures about 100cmThe oral ep. Which measures about 100cm
22

provides a protective surface layer between the provides a protective surface layer between the
oral environment and the dipper tissue.oral environment and the dipper tissue.
The thickness of oral ep. Which is partially The thickness of oral ep. Which is partially
keratinized varies considerably between sites.keratinized varies considerably between sites.
Thickness of epithelium in different regions of oral Thickness of epithelium in different regions of oral
mucosamucosa
Region Region Avg. Thickness Avg. Thickness
umum
SkinSkin 100-120100-120
Hard palateHard palate 250250
Attached gingivaAttached gingiva 200200
Buccal mucosaBuccal mucosa 500-600500-600
Floor of mouthFloor of mouth 100-200100-200

20. Epithelium :Epithelium :

21. ►An imp. feature of oral mucosa is the rapid turnover of cells (3-8 An imp. feature of oral mucosa is the rapid turnover of cells (3-8
days)days)
►It is divided in three functional zones :It is divided in three functional zones :1.Mucus secreting 1.Mucus secreting
regions :- consisting of regions :- consisting of
soft palatesoft palate
the floor of mouththe floor of mouth
under surface of tongueunder surface of tongue
labial andlabial and
buccal mucosabuccal mucosa
having non-keratinized epithelium.having non-keratinized epithelium.
2. Mastcatory mucosa :- consisting of2. Mastcatory mucosa :- consisting of
hard palate hard palate
gingiva gingiva
having keratinized mucosahaving keratinized mucosa

22. 3. Specialized zones :- 3. Specialized zones :-
borders of lipborders of lip
dorsal surface of tongue dorsal surface of tongue
highly selective keratinization.highly selective keratinization.
BIOCHEMICAL COMPOSITIONBIOCHEMICAL COMPOSITION
The composition of the epithelium also The composition of the epithelium also
varies depending on the site in the oral varies depending on the site in the oral
cavity.cavity.
►The mucosae of areas subject to mechanical stress (the The mucosae of areas subject to mechanical stress (the
gingivae and hard palate) are keratinized similar to the gingivae and hard palate) are keratinized similar to the
epidermis.epidermis.
►The keratinized epithelia contain The keratinized epithelia contain neutral lipidsneutral lipids like like
ceramides and acylceramides which have been ceramides and acylceramides which have been
associated with the barrier functionassociated with the barrier function
►These epithelia are relatively impermeable to water.These epithelia are relatively impermeable to water.

23. ►The mucosa of the soft palate, the sublingual, and the The mucosa of the soft palate, the sublingual, and the
buccal regions however, are not keratinizedbuccal regions however, are not keratinized
►In contrast, In contrast, non-keratinizednon-keratinized epithelia, such as the epithelia, such as the
floor of the mouth and the buccal epithelia, do not floor of the mouth and the buccal epithelia, do not
contain acylceramides and only have small amounts contain acylceramides and only have small amounts
of ceramidesof ceramides
►They also contain small amounts of neutral but polar They also contain small amounts of neutral but polar
lipids, mainlylipids, mainly
 cholesterol sulfate and glucosyl ceramidescholesterol sulfate and glucosyl ceramides
►These epithelia have been found to be considerably These epithelia have been found to be considerably
more permeable to water than keratinized epithelia.more permeable to water than keratinized epithelia.

24. Basement membraneBasement membrane
►
AA continuous layer of extra cellular material, continuous layer of extra cellular material,
forming a boundary between the basal layer of forming a boundary between the basal layer of
the epithelium.the epithelium.
►It forms a barrier to the passage of cells across It forms a barrier to the passage of cells across
the mucosa.the mucosa.
lamina proprialamina propria
►Below the basement membrane lies a lamina Below the basement membrane lies a lamina
propria.propria.
►A continuous sheet of connective tissue A continuous sheet of connective tissue
containing collagen, elastic fibers and cellular containing collagen, elastic fibers and cellular
components in a hydrated ground substance.components in a hydrated ground substance.
►It also carries blood capillaries and nerve fibers.It also carries blood capillaries and nerve fibers.

25. ►Basement membraneBasement membrane
The mucosa is the innermost layer of the colon. Major
components of the mucosa include a single layer of
epithelial cells, a layer of connective tissue (the lamina
propria), and a thin muscle layer (the lamina muscularis
mucosae).
The mucosa is lined with goblet cells, which are glands that
secrete mucus to help move material through the colon

26. Secretion of salivaSecretion of saliva
►The surface of mucus membrane is constantly washed The surface of mucus membrane is constantly washed
by a stream of about 0.5-2 L of saliva daily produced in by a stream of about 0.5-2 L of saliva daily produced in
salivary glands i.esalivary glands i.e
►ParotidParotid
►Sub maxillarySub maxillary
►SublingualSublingual
Functions :Functions :
for drug dissolving &for drug dissolving &
for drug permeation.for drug permeation.

27. Vascular system of oral mucosaVascular system of oral mucosa
►The blood flow in various regions of oral mucosa :The blood flow in various regions of oral mucosa :
TissueTissue Blood flow Blood flow
ml/min/100cmml/min/100cm
22
BuccalBuccal 2.402.40
SublingualSublingual 3.143.14
Floor of mouthFloor of mouth0.970.97
Ventral tongueVentral tongue1.171.17
GingivaGingiva 1.471.47
PalatalPalatal 0.890.89

28. Permeability of oral mucosaePermeability of oral mucosae
►It incleudes mainlyIt incleudes mainly
►Regional differences in mucosal permeabilityRegional differences in mucosal permeability
►Transport of material across oral mucosaeTransport of material across oral mucosae
►Membrane storage during buccal absorption of drugMembrane storage during buccal absorption of drug
►Permeability barrier of the oral mucosaePermeability barrier of the oral mucosae

29. Regional differences in mucosal Regional differences in mucosal
permeabilitypermeability
►The permeability of the The permeability of the oraloral mucosae in mucosae in
general is probably intermediate between that general is probably intermediate between that
of epidermis and that of intestinal mucosae.of epidermis and that of intestinal mucosae.
►The permeability of buccal mucosae to be 4-The permeability of buccal mucosae to be 4-
4000 times greater than that of skin.4000 times greater than that of skin.
►Order of permeability : sublingual > buccal > Order of permeability : sublingual > buccal >
palatal.palatal.

30. Transport of material across oral mucosaeTransport of material across oral mucosae
►
TheThe majority of drugs move across epithelial majority of drugs move across epithelial
membranes, including oral epithelia, by passive membranes, including oral epithelia, by passive
mechanisms i.e. by laws of diffusion.mechanisms i.e. by laws of diffusion.
►In case of simple diffusion two potential routes of In case of simple diffusion two potential routes of
material transport across the epithelium are material transport across the epithelium are
- - Para cellular andPara cellular and
- transellular pathways- transellular pathways..

31. TRANSMUCOSAL PERMEABILITYTRANSMUCOSAL PERMEABILITY :-:-
Mechanism transmucosal Mechanism transmucosal
permeation:-permeation:-
Majority of drugs move across Majority of drugs move across
the oral epithelium by passive the oral epithelium by passive
diffusion.diffusion.
In case of simple diffusion, two In case of simple diffusion, two
potential routes of material potential routes of material
transport across the transport across the
epithelium are the –epithelium are the –
11..Transcellular Transcellular (lipoidal (lipoidal
pathway)-lipophilic drugspathway)-lipophilic drugs
2.2.Paracellular Paracellular (Aqueous (Aqueous
pore pathway)-hydrophilic pore pathway)-hydrophilic
drugsdrugs

32. ►The Para cellular route involves the passage of molecules The Para cellular route involves the passage of molecules
through intercellular space while Tran cellular route involves through intercellular space while Tran cellular route involves
transport into and across cells.transport into and across cells.
►Substances with high lipid solubility traverse the oral mucosae Substances with high lipid solubility traverse the oral mucosae
more easily by moving along or across the lipid rich plasma more easily by moving along or across the lipid rich plasma
membrane of the epithelial cells.membrane of the epithelial cells.
►While water soluble substances and ions probably move While water soluble substances and ions probably move
through the intracellular spaces. through the intracellular spaces.

33. Mechanism and kinetics of transmucosal Mechanism and kinetics of transmucosal
permeation:-permeation:-
Based on transmucosal permeation model, the Based on transmucosal permeation model, the
following equation has been developed to following equation has been developed to
describe the apparent permeability coefficient describe the apparent permeability coefficient
PP
appapp==1/(1/P1/(1/P
aa)+[1/(P)+[1/(P
p+p+PP
ll)])]
where,where,
PP
a,a, P P
p,p, P P
l l are the permeability coefficient across are the permeability coefficient across
the aqueous diffusion layer,aqueous pore the aqueous diffusion layer,aqueous pore
pathway and the lipoidal pathway respectively.pathway and the lipoidal pathway respectively.

34. Permeability barrier of the oral mucosaPermeability barrier of the oral mucosa
►For the purpose of drug delivery, it is assumed that For the purpose of drug delivery, it is assumed that
non- keratinized lining mucosa are preferable to the non- keratinized lining mucosa are preferable to the
keratinized regions.keratinized regions.
►Keratin layerKeratin layer is an effective barrier to penetration of is an effective barrier to penetration of
human skin by water soluble substances.human skin by water soluble substances.
►The permeability barrier of oral mucosa is reside within The permeability barrier of oral mucosa is reside within
the superficial layers of the epithelium.the superficial layers of the epithelium.

35. Keratin layerKeratin layer
•Profile of different tissue sites within the oral cavity
exposed to saliva including hard palate, alveolar ridge,
gingiva, and buccal mucosa

36. ►Also some workers suggest that the Also some workers suggest that the basement basement
membranemembrane is the functional permeation barrier of the is the functional permeation barrier of the
oral mucosa or that it represent at least degree of oral mucosa or that it represent at least degree of
resistance to permeates.resistance to permeates.
►The The lamina proprialamina propria is not generally thought to present a is not generally thought to present a
barrier to permeation.barrier to permeation.
►Another barrier for large water soluble molecules in Another barrier for large water soluble molecules in
both keratinized and non keratinized epithelia is both keratinized and non keratinized epithelia is
‘‘Membrane Coating Granules’(MCG).Membrane Coating Granules’(MCG).
►MCG are spherical or oval organelles, having 100-300 MCG are spherical or oval organelles, having 100-300
nm in diameter and are found in intermediate cell layers nm in diameter and are found in intermediate cell layers
of many stratified epithelia.of many stratified epithelia.

37. ►MCG are involved in development of intracellular matrix (itself MCG are involved in development of intracellular matrix (itself
or its released contents) which is responsible for permeability of or its released contents) which is responsible for permeability of
mucosa particular in Para cellular route.mucosa particular in Para cellular route.
►Other factors which may affect the permeability of molecule:Other factors which may affect the permeability of molecule:
Exogenous substances placed in mouth Exogenous substances placed in mouth
►E.g.. Mouthwashes , toothpaste. E.g.. Mouthwashes , toothpaste.

38. MUCOSAL MEMBRANE MODELSMUCOSAL MEMBRANE MODELS ::
The The fluid mosaic modelfluid mosaic model was proposed by was proposed by Singer and Singer and
Nicolson.Nicolson.

Fluid mosaic model consists of Fluid mosaic model consists of Amphipathic globular integral Amphipathic globular integral
proteinsproteins that are embedded in the fluid state of lipid bilayer / that are embedded in the fluid state of lipid bilayer /
span throughout the entire thickness.span throughout the entire thickness.

These proteins have been hypothesized to These proteins have been hypothesized to minimize the free minimize the free
energy required for the transmembrane permeationenergy required for the transmembrane permeation by by
maximizing both the hydrophilic and lipophilic interactions in maximizing both the hydrophilic and lipophilic interactions in
the membrane.the membrane.

The ionic and polar portion of the protein molecule are remain The ionic and polar portion of the protein molecule are remain
in contact with the aqueous environment on the membrane in contact with the aqueous environment on the membrane
surface and its relatively non-polar portion is interact with surface and its relatively non-polar portion is interact with
the alkyl chain in the lipid bilayer.the alkyl chain in the lipid bilayer.

39. Figure:-The fluid mosaic model was proposed by Singer and Figure:-The fluid mosaic model was proposed by Singer and
Nicolson for the structure of epithelial membrane, which Nicolson for the structure of epithelial membrane, which
consists of Amphipathic globular integral proteins:-consists of Amphipathic globular integral proteins:-
Amphipathic
globular integral
protein

42. Two thermodynamically favored structures Two thermodynamically favored structures
of the globular integral protein molecule:of the globular integral protein molecule:
Fig: Monodisperse structure Fig: Monodisperse structure
in which the hydrophilic in which the hydrophilic
component (H) is component (H) is
exposed to the aqueous exposed to the aqueous
environment on the environment on the
surface of epithelial surface of epithelial
membrane and the membrane and the
lipophilic component (L) lipophilic component (L)
is embedded in the lipid is embedded in the lipid
bilayer.bilayer.

43. Fig: Subunit aggregate Fig: Subunit aggregate
structure in which a structure in which a
subunit aggregate of subunit aggregate of
two protein molecules two protein molecules
spanning through the spanning through the
entire thickness of the entire thickness of the
lipid bilayer to form an lipid bilayer to form an
aqueous solution filled aqueous solution filled
pore channel.pore channel.

44. Ion channelIon channel

45. Strategy to increase penetration Strategy to increase penetration
►Success of all Tran mucosal systems depends on the Success of all Tran mucosal systems depends on the
ability of drug to penetrate mucosa in sufficient ability of drug to penetrate mucosa in sufficient
quantities to achieve its desired therapeutic effect.quantities to achieve its desired therapeutic effect.
►Attention is mainly focused on use of penetration Attention is mainly focused on use of penetration
enhancer for enhancing the permeability of the oral enhancer for enhancing the permeability of the oral
mucosa.mucosa.

46. PERMEABILITY ENHANCERS:PERMEABILITY ENHANCERS:
These are chemicals which disturb the membrane integrity, These are chemicals which disturb the membrane integrity,
affecting increased permeation of drug through buccal mucosa.affecting increased permeation of drug through buccal mucosa.
Permeability of buccal mucosa can be increased by various Permeability of buccal mucosa can be increased by various
penetration enhancers capable of -penetration enhancers capable of -
►increasing cell membrane fluidityincreasing cell membrane fluidity
►extracting the structural intercellular/intracellular lipidsextracting the structural intercellular/intracellular lipids
►altering cellular proteinsaltering cellular proteins
►altering mucus structure and rheologyaltering mucus structure and rheology
Examples:-Examples:-
►Bile salts- sod.glycholate, sod.deoxycholateBile salts- sod.glycholate, sod.deoxycholate
►Fatty acids-lauric acid ,oleic acid.Fatty acids-lauric acid ,oleic acid.
►Sodium lauryl sulpfate,cetyl pyridinium Sodium lauryl sulpfate,cetyl pyridinium
chloride,cyclodextrin,propylene glycol,sulfoxideschloride,cyclodextrin,propylene glycol,sulfoxides

47. ►The steady state flux of a lipophilic drug (T) across the transcellular route is given by-The steady state flux of a lipophilic drug (T) across the transcellular route is given by-
JJ
T T = (1-M) D= (1-M) D
TTKK
P .P .CC
DD
hh
pp
Where M=area fraction of transcellular routeWhere M=area fraction of transcellular route
DD
TT==
diffusion coefecient in the lipophilic phasediffusion coefecient in the lipophilic phase
KK
PP==
partition coefficient between lipophilic & aqueous hydrophilic partition coefficient between lipophilic & aqueous hydrophilic donor donor
phasephase
CC
DD==
conc. of drug in donor chamberconc. of drug in donor chamber
hh
pp=length of the transcellular route=length of the transcellular route
► The steady state flux of a hydrophilic drug (H) across the paracellular route is given by-The steady state flux of a hydrophilic drug (H) across the paracellular route is given by-
JJ
HH = D = D
PPMM
. . CC
DD
hh
pp
Where M=area fraction of transcellular routeWhere M=area fraction of transcellular route
DD
pp==
diffusion coefecient in the lipophilic phasediffusion coefecient in the lipophilic phase
CC
DD==
conc. of drug in donor chamberconc. of drug in donor chamber
hh
pp=length of the transcellular route=length of the transcellular route

48. Sources of VariabilitySources of Variability
1.Animals
2. Tissue thickness (connective tissue)
3. Excision method/ preparation
4. Storage conditions
5. Experimental temperature
Validate prep/ handling methods

49. InvitroInvitro and and invivoinvivo methods of buccal absorption methods of buccal absorption::
InvitroInvitro methods: methods:

50. Invivo Invivo methods:methods:
Perfusion cell :Perfusion cell :

51. ►Other in vivo methods include those carried out usingOther in vivo methods include those carried out using
►a a small perfusion chambersmall perfusion chamber attached to the upper lip of attached to the upper lip of
anesthetized dogs . anesthetized dogs .
►The perfusion chamber is attached to the tissue by The perfusion chamber is attached to the tissue by
cyanoacrylate cement.cyanoacrylate cement.
► The drug solution is circulated through the device for a The drug solution is circulated through the device for a
predetermined period of time and sample fractions arepredetermined period of time and sample fractions are
then collected from the then collected from the perfusion chamberperfusion chamber (to determine the (to determine the
amount of drug remaining in the chamber) and amount of drug remaining in the chamber) and blood blood samples samples
are drawn after 0 and 30 minutes (to determine amount of drug are drawn after 0 and 30 minutes (to determine amount of drug
absorbed across the mucosa).absorbed across the mucosa).

52. Absorption cellAbsorption cell
►
TheThe simplest absorption cell is a rubber ‘O’ ring with internal simplest absorption cell is a rubber ‘O’ ring with internal
diameter 2.64 mm was fixed to the ventral surface of tongue of diameter 2.64 mm was fixed to the ventral surface of tongue of
adult male Sprague Dawley rats using a cynanoacrylate adult male Sprague Dawley rats using a cynanoacrylate
adhesive.adhesive.
►10 ml of radiolabelled substance dissolved in a suitable buffer 10 ml of radiolabelled substance dissolved in a suitable buffer
was placed into the ring and absorption characteristics was placed into the ring and absorption characteristics
determined by blood levels and test solution in ‘O’ ring.determined by blood levels and test solution in ‘O’ ring.

53. ►Buccal Absorption Test:Buccal Absorption Test:
►Using this method, the kinetics of drug absorption Using this method, the kinetics of drug absorption
were measured.were measured.
►The methodology involves the :The methodology involves the :
►swirling of a 25 ml sample of the test solution for up swirling of a 25 ml sample of the test solution for up
toto
15 minutes by human volunteers followed by the15 minutes by human volunteers followed by the
expulsion of the solution. expulsion of the solution.
► The amount of drug remaining in the expelled The amount of drug remaining in the expelled
volume is then determined in order to assess the volume is then determined in order to assess the
amount of drug absorbed. amount of drug absorbed.

54. ►The The drawbacksdrawbacks of this method include:of this method include:
► salivary dilution of the drug, salivary dilution of the drug,
►accidental swallowing of a portion of the accidental swallowing of a portion of the
sample solution, sample solution,
►and the inability to localize the drug and the inability to localize the drug
solution within a specific site (buccal, solution within a specific site (buccal,
sublingual, or gingival) of the oral cavity.sublingual, or gingival) of the oral cavity.

55. Present LandscapePresent Landscape
“At least” 50 US Patents issued*
Generex - Insulin, “Ora-lyn”
- LMW Heparin
- Fentanyl
-Morphine
Novadel - Nitroglycerin
- Sumatriptan
- Zolpidem
- Ondansetron
*Drug Delivery to the Oral Cavity - T.K. Ghosh & W.R.
Pfister (eds.)

56. REFERENCESREFERENCES::
1.1.Novel drug delivery systems by Yie.W.Chien. pg:197-228.Novel drug delivery systems by Yie.W.Chien. pg:197-228.
2.2.Controlled and novel drug delivery by N.K.Jain. pg:52-74.Controlled and novel drug delivery by N.K.Jain. pg:52-74.
3.3.Advances in controlled and novel drug delivery by N.K.Jain. Advances in controlled and novel drug delivery by N.K.Jain.
pg:70-82.pg:70-82.
4.4.Indian journal of pharmaceutical sciences.Indian journal of pharmaceutical sciences.
5.5.www.google.comwww.google.com..
6.6.www.elsevier.comwww.elsevier.com

61. Tablet Fabrication
Core tablet
Drug, Hakea, excipients
Coated tablet
Core tablet compression coated
- except one flat face
H.H. Alur, J.D. Beal, S.I. Pather,
A.K. Mitra and T.P. Johnston.
J. Pharm. Sci. 88 (1999) 1313-
1319.

62. ►Salmon Calcitonin (sCT)Salmon Calcitonin (sCT)
►• • Responsible for lowering serum calciumResponsible for lowering serum calcium
►• • MW = 3432 DaMW = 3432 Da
►• • Used to treat Paget’s disease,Used to treat Paget’s disease,
►hypercalcemia, and osteoporosishypercalcemia, and osteoporosis
►• • Available as injection and nasal sprayAvailable as injection and nasal spray

63. ►Cys-Ser-Asn-Leu-Ser-Thr-Cys-Cys-Ser-Asn-Leu-Ser-Thr-Cys-
►Val-Leu-Gly-Lys-Leu-Ser-Gln-Val-Leu-Gly-Lys-Leu-Ser-Gln-
►Glu-Leu-His-Lys-Leu-Gln-Thr-Glu-Leu-His-Lys-Leu-Gln-Thr-
►Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-
►Ser-Gly-Thr-Pro-NH2Ser-Gly-Thr-Pro-NH2
►1 71 7
►STRUCTURE OF CALCITONINSTRUCTURE OF CALCITONIN
►(32 amino acid polypeptide with a disulfide (32 amino acid polypeptide with a disulfide
bridgebridge
►between cysteine residues 1 and 7).between cysteine residues 1 and 7).

64. ►Bioadhesive StrengthBioadhesive Strength
►Rabbit intestinal mucosaRabbit intestinal mucosa
►Medium: 20 μl of distilled water (pH = 7.0)Medium: 20 μl of distilled water (pH = 7.0)
►Chatillion LTC universal tension-compression standChatillion LTC universal tension-compression stand
►with DFM-10 digital force gaugewith DFM-10 digital force gauge
►Force of compression: 5, 10, 15, and 20 N.Force of compression: 5, 10, 15, and 20 N.
►Duration of application: 5, 10, 20, 30, 45, 60 and 90Duration of application: 5, 10, 20, 30, 45, 60 and 90
►min.min.
►Applied to tablets containing 0, 12 or 32 mg HakeaApplied to tablets containing 0, 12 or 32 mg Hakea

65. ►In vitro sCT ReleaseIn vitro sCT Release
►• • Apparatus: Jacketed glass vesselApparatus: Jacketed glass vessel
►• • Medium: Deionized Water, 200 mlMedium: Deionized Water, 200 ml
►• • pH: 7.0 ± 0.1pH: 7.0 ± 0.1
►• • Temperature: 37° CTemperature: 37° C
►• • Analysis: Enzyme Immuno Assay (EIAH)Analysis: Enzyme Immuno Assay (EIAH)
►after appropriate dilution.after appropriate dilution.

66. ►Animal ModelAnimal Model
►New Zealand white Rabbits (2.7 ± 0.4 kg)New Zealand white Rabbits (2.7 ± 0.4 kg)
►Anesthesia - xylazine (1.9 mg/kg) andAnesthesia - xylazine (1.9 mg/kg) and
►ketamine (9.3 mg /kg) (I.M.)ketamine (9.3 mg /kg) (I.M.)
►Blood sampling - marginal ear veinBlood sampling - marginal ear vein

67. ►In vivo sCT StudyIn vivo sCT Study
►• • Dose - 40 μg (200 I.U.)Dose - 40 μg (200 I.U.)
►• • Tablet moistened and compressed ontoTablet moistened and compressed onto
►buccal areabuccal area
►• • sCT analysis - Enzyme Immuno Assay sCT analysis - Enzyme Immuno Assay
(EIAH)(EIAH)
►• • Calcium analysis - o-CresolpthaleinCalcium analysis - o-Cresolpthalein
►complexone methodcomplexone method

68. ►Enzyme Activity StudiesEnzyme Activity Studies
►• • Mucosal enzymes degrade peptidesMucosal enzymes degrade peptides
►• • Rates of enzyme activity with andRates of enzyme activity with and
►without Hakea studiedwithout Hakea studied
►• • Evidence that Hakea inhibits enzymesEvidence that Hakea inhibits enzymes

69. ►ConclusionsConclusions
►• • Hakea is a promising additiveHakea is a promising additive
►– – sustained-releasesustained-release
►– – mucoadhesive propertiesmucoadhesive properties
►– – decreased rate of enzymatic decreased rate of enzymatic
degradationdegradation
►• • Improved transbuccal delivery systemImproved transbuccal delivery system

72. SEMINAR IN SEMINAR IN
ADVANCES IN DRUG DELIVERY ADVANCES IN DRUG DELIVERY
SYSTEMSSYSTEMS
TOPIC -TOPIC -
MUCOADHESIVE DRUG DELIVERY MUCOADHESIVE DRUG DELIVERY
SYSTEMSYSTEM

73. ContentsContents::

Buccal drug delivery systemsBuccal drug delivery systems

ConceptsConcepts
Advantages and disadvantagesAdvantages and disadvantages

Structure of oral mucosaStructure of oral mucosa
Transmucosal permeabilityTransmucosal permeability

Mucosal membrane modelsMucosal membrane models

Permeability enhancersPermeability enhancers

InvitroInvitro and and invivoinvivo methods of buccal absorption methods of buccal absorption

74. Drug delivery via the membranes of Drug delivery via the membranes of
the oral cavity can be sub the oral cavity can be sub
divided as follows:divided as follows:
1.1.Sublingual delivery. Sublingual delivery.
2.2.Buccal delivery. Buccal delivery.
3.3.Local delivery. Local delivery.
AIMS AND OBJECTIVES:AIMS AND OBJECTIVES:
► Improve patient complianceImprove patient compliance
► Avoid first pass metabolismAvoid first pass metabolism
► Reduce side effects which Reduce side effects which
occur when given by other occur when given by other
routes.routes.
► Reduce pulsed entry and Reduce pulsed entry and
controls drug appearance in controls drug appearance in
plasma/systemic circulation.plasma/systemic circulation.

75. BUCCAL DRUG DELIVERY SYSTEMS:BUCCAL DRUG DELIVERY SYSTEMS:
Definition:- These may be defined as the drug delivery systems Definition:- These may be defined as the drug delivery systems
which when applied on intact mucous membrane of oral cavity, which when applied on intact mucous membrane of oral cavity,
the passage of drug occurs at a controlled rate into systemic the passage of drug occurs at a controlled rate into systemic
circulation.circulation.
Various buccal mucoadhesive dosage forms are -Various buccal mucoadhesive dosage forms are -
►Buccal Tablets Buccal Tablets
►Buccal PatchesBuccal Patches
►Buccal FilmsBuccal Films
►Buccal Gels Buccal Gels
►Buccal Ointments Buccal Ointments

76. Ideal characteristics of BDDSIdeal characteristics of BDDS::
►should be adhesive enough to be retained on the buccal should be adhesive enough to be retained on the buccal
mucosa for atleast upto 6hours.mucosa for atleast upto 6hours.
►should be non irritant and non allergenic.should be non irritant and non allergenic.
►Size of the patch may be 1-5cmSize of the patch may be 1-5cm
2 2
but should be 1-3cmbut should be 1-3cm
22
to be to be
comfortablecomfortable

to the to the

patientspatients

..
►should restrict the rate of water ingress.should restrict the rate of water ingress.

77. Components of BDDS:Components of BDDS:
►DrugDrug
►PolymerPolymer
Drug properties:Drug properties:
►Conventional single dose of the drug should be low.Conventional single dose of the drug should be low.
►Should not have bitter taste and obnoxious odour.Should not have bitter taste and obnoxious odour.
►Should be non allergenic and non irritantShould be non allergenic and non irritant
►Should have low mol.wtShould have low mol.wt
►Oral bioavailability should be less.Oral bioavailability should be less.
Polymer propertiesPolymer properties::
►Should have good bioadhesive property.Should have good bioadhesive property.
►Should be non allergenic and non irritantShould be non allergenic and non irritant
►Should have high mol.wt.Should have high mol.wt.
►Should be compatible with the drugShould be compatible with the drug
►Should be stable and economicShould be stable and economic

78. Three different categories of polymersThree different categories of polymers::
Bioadhesive polymer-Bioadhesive polymer-
Egs: carbopol 934,HPMC,CMC,Sodium CMC, PVP,PVA, Egs: carbopol 934,HPMC,CMC,Sodium CMC, PVP,PVA,
chitosan, starch. chitosan, starch.
Rate controlling polymer-Rate controlling polymer-
Egs: ethyl cellulose and Eudragit.Egs: ethyl cellulose and Eudragit.
Backing membrane polymer-Backing membrane polymer-
Egs: polyglassine and cellulose acetate.Egs: polyglassine and cellulose acetate.

80. Concept:Concept:
For systemic delivery ,the oral route has been the most For systemic delivery ,the oral route has been the most
preferred route of administration. When administered preferred route of administration. When administered
by oral route many drugs are subjected to extensive by oral route many drugs are subjected to extensive
presystemic elimination by gastrointestinal degradation presystemic elimination by gastrointestinal degradation
or hepatic metabolism.or hepatic metabolism.
Delivery of drugs via the absorptive mucosa in various, Delivery of drugs via the absorptive mucosa in various,
easily accessible body cavities like the buccal, ocular, easily accessible body cavities like the buccal, ocular,
nasal, rectal and vaginal mucosae has the advantage of nasal, rectal and vaginal mucosae has the advantage of
bypassing the hepato-gatrointestinal first pass bypassing the hepato-gatrointestinal first pass
elimination. elimination.
With the development of mucosal drug delivery system With the development of mucosal drug delivery system
having controlled drug release characteristics, the having controlled drug release characteristics, the
mucosal routes can be exploited for the noninvasive mucosal routes can be exploited for the noninvasive
systemic delivery of organic and peptide based drugs, systemic delivery of organic and peptide based drugs,
with rapid drug absorption and sustained action.with rapid drug absorption and sustained action.

81. ADVANTAGES:ADVANTAGES:
Avoids first pass metabolism.Avoids first pass metabolism.
Drugs degraded in GIT can be given by this route. Drugs degraded in GIT can be given by this route.
Eg: Insulin and other proteins.Eg: Insulin and other proteins.
Fast onset of action.Fast onset of action.
Permits localization of drug action. Permits localization of drug action.
It is a passive system.It is a passive system.
Can be made unidirectional to ensure only buccal absorption. Can be made unidirectional to ensure only buccal absorption.
Can be removed in cases of emergency.Can be removed in cases of emergency.
Provides greater permeability.Provides greater permeability.
Bioavailability is increased and dosing frequency is reducedBioavailability is increased and dosing frequency is reduced
Dose is reduced.Dose is reduced.
Reduces the side effects.Reduces the side effects.
Can be given to nauseating and unconscious patients.Can be given to nauseating and unconscious patients.

82. Oral mucosa is an robust membrane that is less prone Oral mucosa is an robust membrane that is less prone
to irreversible damage caused by drugs and additives.to irreversible damage caused by drugs and additives.
Both hydrophilic and lipophilic drugs can be given.Both hydrophilic and lipophilic drugs can be given.
Advantages of the oral cavity as a site for systemic drug Advantages of the oral cavity as a site for systemic drug
delivery are:-delivery are:-
►Sterilization is not required.Sterilization is not required.
►Enzymatic degradation is relatively low.Enzymatic degradation is relatively low.
►Oral cavity contains teeth upon which the DDS can be Oral cavity contains teeth upon which the DDS can be
physically attached using adhesives. physically attached using adhesives.

..

83. DISADVANTAGES:DISADVANTAGES:

Drugs which undergo metabolism in oral cavity cannot be Drugs which undergo metabolism in oral cavity cannot be
given.given.

Drugs which are bitter, obnoxious odour and irritant to the oral Drugs which are bitter, obnoxious odour and irritant to the oral
mucosa cannot be given.mucosa cannot be given.

Oral mucosa has small surface area for drug absorption Oral mucosa has small surface area for drug absorption
compared to GIT.compared to GIT.

Patient finds difficult to eat, drink or talk.Patient finds difficult to eat, drink or talk.

Patient can swallow the dosage form accidentally.Patient can swallow the dosage form accidentally.

Only drugs with a dose less than 25mg can be given as BDDS.Only drugs with a dose less than 25mg can be given as BDDS.

84. Factors affecting buccal membrane absorption:Factors affecting buccal membrane absorption:
Membrane factors:-Membrane factors:-
►Degree of keratinisationDegree of keratinisation
►Surface area available for absorptionSurface area available for absorption
►Salivary film coat on mucous membraneSalivary film coat on mucous membrane
►Intercellular lipids of the epitheliumIntercellular lipids of the epithelium
►Basement membrane or lamina propriaBasement membrane or lamina propria
►Absorptive membrane thicknessAbsorptive membrane thickness
►Blood supply/ cell renewal/ enzyme contentBlood supply/ cell renewal/ enzyme content
Environmental factors:Environmental factors:
►Saliva:-Saliva:-
thickness of salivary film- 0.07 - 0.10mm thickness of salivary film- 0.07 - 0.10mm
►Salivary glands:- Salivary glands:-
pH= 6.2 - 7.4pH= 6.2 - 7.4
►Movement of oral tissuesMovement of oral tissues

85. STRUCTURE OF THE ORAL STRUCTURE OF THE ORAL
MUCOSA:-MUCOSA:-

86. TRANSMUCOSAL PERMEABILITYTRANSMUCOSAL PERMEABILITY :-:-
Mechanism transmucosal Mechanism transmucosal
permeation:-permeation:-
Majority of drugs move across Majority of drugs move across
the oral epithelium by passive the oral epithelium by passive
diffusion.diffusion.
In case of simple diffusion, two In case of simple diffusion, two
potential routes of material potential routes of material
transport across the transport across the
epithelium are the –epithelium are the –
11..Transcellular Transcellular (lipoidal (lipoidal
pathway)-lipophilic drugspathway)-lipophilic drugs
2.2.Paracellular Paracellular (Aqueous (Aqueous
pore pathway)-hydrophilic pore pathway)-hydrophilic
drugsdrugs

87. Mechanism and kinetics of transmucosal Mechanism and kinetics of transmucosal
permeation:-permeation:-
Based on transmucosal permeation model, the following Based on transmucosal permeation model, the following
equation has been developed to describe the apparent equation has been developed to describe the apparent
permeability coefficient permeability coefficient
PP
appapp==1/(1/P1/(1/P
aa)+[1/(P)+[1/(P
p+p+PP
ll)])]
where,where,
PP
a,a, P P
p,p, P P
l l are the permeability coefficient across the are the permeability coefficient across the
aqueous diffusion layer,aqueous pore pathway and the aqueous diffusion layer,aqueous pore pathway and the
lipoidal pathway respectively.lipoidal pathway respectively.

88. MUCOSAL MEMBRANE MODELS:MUCOSAL MEMBRANE MODELS:
The The fluid mosaic modelfluid mosaic model was proposed by was proposed by Singer and Singer and
NicolsonNicolson..

Fluid mosaic model consists of amphipathic globular Fluid mosaic model consists of amphipathic globular
integral proteins that are embedded in the fluid state of integral proteins that are embedded in the fluid state of
lipid bilayer / span throughout the entire thickness.lipid bilayer / span throughout the entire thickness.

These proteins have been hypothesized to These proteins have been hypothesized to minimize the minimize the
free energy required for the transmembrane free energy required for the transmembrane
permeationpermeation by maximizing both the hydrophilic and by maximizing both the hydrophilic and
lipophilic interactions in the membrane.lipophilic interactions in the membrane.

The ionic and polar portion of the protein molecule are The ionic and polar portion of the protein molecule are
in contact with the aqueous environment on the in contact with the aqueous environment on the
membrane surface and the non-polar portion of the membrane surface and the non-polar portion of the
protein is towards the interior which interact with the protein is towards the interior which interact with the
alkyl chain in the lipid bilayer.alkyl chain in the lipid bilayer.

89. Figure:-The fluid mosaic model was proposed by Singer and Figure:-The fluid mosaic model was proposed by Singer and
Nicolson for the structure of epithelial membrane, which Nicolson for the structure of epithelial membrane, which
consists of amphipathic globular integral proteins:-consists of amphipathic globular integral proteins:-

90. Two thermodynamically favored structures Two thermodynamically favored structures
of the globular integral protein molecule:of the globular integral protein molecule:
Fig: Monodisperse structure Fig: Monodisperse structure
in which the hydrophilic in which the hydrophilic
component (H) is component (H) is
exposed to the aqueous exposed to the aqueous
environment on the environment on the
surface of epithelial surface of epithelial
membrane and the membrane and the
lipophilic component (L) lipophilic component (L)
is embedded in the lipid is embedded in the lipid
bilayer.bilayer.

91. Fig: Subunit aggregate Fig: Subunit aggregate
structure in which a structure in which a
subunit aggregate of subunit aggregate of
two protein molecules two protein molecules
spanning through the spanning through the
entire thickness of the entire thickness of the
lipid bilayer to form an lipid bilayer to form an
aqueous solution filled aqueous solution filled
pore channel.pore channel.

92. PERMEABILITY ENHANCERS:PERMEABILITY ENHANCERS:
These are chemicals which disturb the membrane integrity, These are chemicals which disturb the membrane integrity,
affecting increased permeation of drug through buccal mucosa.affecting increased permeation of drug through buccal mucosa.
Permeability of buccal mucosa can be increased by various Permeability of buccal mucosa can be increased by various
penetration enhancers capable of -penetration enhancers capable of -
►increasing cell membrane fluidityincreasing cell membrane fluidity
►extracting the structural intercellular/intracellular lipidsextracting the structural intercellular/intracellular lipids
►altering cellular proteinsaltering cellular proteins
►altering mucus structure and rheologyaltering mucus structure and rheology
Examples:-Examples:-
►Bile salts- sod.glycholate, sod.deoxycholateBile salts- sod.glycholate, sod.deoxycholate
►Fatty acids-lauric acid ,oleic acid, eicosapentaenoic acidFatty acids-lauric acid ,oleic acid, eicosapentaenoic acid
►Sodium lauryl sulpfate,cetyl pyridinium Sodium lauryl sulpfate,cetyl pyridinium
chloride,cyclodextrin,propylene glycol,sulfoxideschloride,cyclodextrin,propylene glycol,sulfoxides

93. ►The steady state flux of a lipophilic drug (T) across the transcellular route is given by-The steady state flux of a lipophilic drug (T) across the transcellular route is given by-
JJ
T T = (1-M) D= (1-M) D
TTKK
P .P .CC
DD
hh
pp
Where M=area fraction of transcellular routeWhere M=area fraction of transcellular route
DD
TT==
diffusion coefecient in the lipophilic phasediffusion coefecient in the lipophilic phase
KK
PP==
partition coefficient between lipophilic & aqueous hydrophilic partition coefficient between lipophilic & aqueous hydrophilic donor donor
phasephase
CC
DD==
conc. of drug in donor chamberconc. of drug in donor chamber
hh
pp=length of the transcellular route=length of the transcellular route
► The steady state flux of a hydrophilic drug (H) across the paracellular route is given by-The steady state flux of a hydrophilic drug (H) across the paracellular route is given by-
JJ
HH = D = D
PPMM
. . CC
DD
hh
pp
Where M=area fraction of transcellular routeWhere M=area fraction of transcellular route
DD
pp==
diffusion coefecient in the lipophilic phasediffusion coefecient in the lipophilic phase
CC
DD==
conc. of drug in donor chamberconc. of drug in donor chamber
hh
pp=length of the transcellular route=length of the transcellular route

94. InvitroInvitro and and invivoinvivo methods of buccal absorption methods of buccal absorption::
InvitroInvitro methods: methods:

95. Invivo Invivo methods:methods:

96. THERAPEUTIC APPLICATIONS:-THERAPEUTIC APPLICATIONS:-
Angina – Organic and nitrate compoundsAngina – Organic and nitrate compounds
Acute seizures; asthma & allergyAcute seizures; asthma & allergy
Chronic severe painChronic severe pain
Migraine; hypertensionMigraine; hypertension
Smoking cessation; alcohol abuseSmoking cessation; alcohol abuse
Hormonal treatmentsHormonal treatments
Diabetes – Emerging indication for TM deliveryDiabetes – Emerging indication for TM delivery
TM delivery of traditional drugs; proteins, peptides, vaccinesTM delivery of traditional drugs; proteins, peptides, vaccines

101. REFERENCES:REFERENCES:
1.1.Novel drug delivery systems by Yie.W.Chien. Novel drug delivery systems by Yie.W.Chien.
pg:197-228pg:197-228
2.2.Controlled and novel drug delivery by N.K.Jain. Controlled and novel drug delivery by N.K.Jain.
pg:52-74pg:52-74
3.3.Advances in controlled and novel drug delivery by Advances in controlled and novel drug delivery by
N.K.Jain. pg:70-82N.K.Jain. pg:70-82
4.4.Indian journal of pharmaceutical sciencesIndian journal of pharmaceutical sciences
5.5.Indian drugsIndian drugs
6.6.www.google.comwww.google.com
7.7.www.elsevier.comwww.elsevier.com